Imidazopyridyl compounds as aldosterone synthase inhibitors

ABSTRACT

This invention relates to imidazopyridyl compounds of the structural formula: I or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.

RELATED APPLICATION

This application claims benefit to provisional application U.S. Ser. No.61/537,910, filed 22 Sep. 2012, herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to imidazopyridyl compounds, whichselectively inhibit aldosterone synthase (CYP11B2) with diminishedinhibition or affect on steroid-11-β-hydroxylase (CYP11B1) inhibitors.The inventive compounds potentially have utility in treatingcardiovascular diseases such as hypertension or heart failure. Thepresent invention also relates to pharmaceutical compositions comprisingthe inventive compounds as well as processes for their preparation.

BACKGROUND OF THE INVENTION

Aldosterone is a steroid hormone secreted in the adrenal cortex. Inprimary cells of the distal tubules and collecting ducts of the kidney,aldosterone binding to the mineralocorticoid receptor (MR) results inthe retention of sodium and water and excretion of potassium, which inturn leads to increased blood pressure. Aldosterone also causesinflammation that leads to fibrosis and remodeling in the heart,vasculature and kidney. This inflammation may proceed by MR-dependent aswell as MR-independent mechanisms (Gilbert, K. C. et al., Curr. Opin.Endocrinol. Diabetes Obes., vol. 17, 2010, pp. 199-204).

Mineralocorticoid receptor antagonists (MRAs), such as spironolactoneand eplerenone, have been used previously to block the effects ofaldosterone binding to MR. When given in addition to standard therapiessuch as angiotensin-converting enzyme (ACE) inhibitors and loopdiuretics, the nonselective MRA spironolactone and the selective MRAeplerenone significantly reduced morbidity and mortality in patientswith heart failure or myocardial infarction (Pitt, B. et al., New Engl.J. Med., vol. 341, 1999, pp. 709-717; Pitt, B. et al., New Engl. J.Med., vol. 348, 2003, pp. 1382-1390). However, the nonselective MRAspironolactone can also bind to and act at other steroid receptors, andas a consequence its use is associated with sexual side effects such asgynecomastia, dysmenorrhoea and impotence (Pitt, B. et al., New Engl. J.Med., vol. 341, 1999, pp. 709-717; MacFadyen, R. J. et al., Cardiovasc.Res., vol. 35, 1997, pp 30-34; Soberman, J. E. et al., Curr. Hypertens.Rep., vol. 2, 2000, pp 451-456). Additionally, both spironolactone andeplerenone are known to cause elevated plasma postassium levels(hyperkalemia) and elevated aldosterone levels.

An alternative method of blocking the effects of aldosterone is toinhibit its biosynthesis. CYP11B2 is a mitochondrial cytochrome P450enzyme that catalyzes the final oxidative steps in the conversion of11-deoxycorticosterone, a steroidal precursor, to aldosterone (Kawamoto,T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992, pp. 1458-1462).Compounds that inhibit CYP11B2 should thus inhibit the formation ofaldosterone. Such compounds, particularly those of nonsteroidalstructure, should provide the beneficial effects of MRAs, without theadverse effects derived from steroid receptor binding or MR-independentinflammatory pathways. The art has recognized that reducing aldosteronelevels by inhibiting aldosterone synthase could represent a newpharmaceutical strategy that might be useful in treating a disorder ordisease characterized by increased stress hormone levels and/ordecreased androgen hormone levels in a patient (WO2011/088188 toNovartis). Compounds possessing this activity might have the potentialto treat disease states such as heart failure, cachexia, acute coronarysyndrome, Cushing's syndrome or metabolic syndrome.

CYP11B1 is a related enzyme that catalyzes the formation ofglucocorticoids, such as cortisol, an important regulator of glucosemetabolism. Because human CYP11B2 and CYP11B1 are greater than 93%homologous, it is possible for nonselective compounds to inhibit bothenzymes (Kawamoto, T. et al., Proc. Natl. Acad. Sci. USA, vol. 89, 1992,pp 1458-1462; Taymans, S. E. et al., J. Clin. Endocrinol. Metab., vol.83, 1998, pp 1033-1036). It would be preferable, however, fortherapeutic agents to selectively inhibit CYP11B2 and the formation ofaldosterone with diminished inhibition of, or affect on, CYP11B1 and theproduction of cortisol.

WO 2009/135651 to Elexopharm describes6-pyridin-3yl-3,4,-dihydro-1H-quinolin-2-one derivatives as beingCYP11B2 inhibitors. Two compounds described therein are lactamderivatives of the formula:

Structurally similar lactam and thiolactam compounds are disclosed byLucas et al., J. Med. Chem. 2008, 51, 8077-8087; those compounds aresaid to be potential inhibitors of CYP11B2. Lucas et al. in J. Med.Chem. 2011, 54, 2307-2309 describes certain pyridine substituted3,4-dihydro-1H-quinolin-2-ones as being highly potent as selectiveinhibitors of CYP11B2. An abstract of a dissertation reports that aseries of novel heterocyclic-substituted4,5-dihydro-[1,2,4]triazolo[4,3a]quinolones was evaluated for itsaldosterone synthase activity; one of the compounds is reported asexhibiting excellent selectivity of CYP11B2 over CYP11B1.

Benzimidazole derivatives are also known in the art to treat variousdisease states. For example, U.S. Pat. No. 6,897,208 to AventisPharmaceuticals describes compounds of the formula:

wherein R¹ is an optionally substituted aryl or heteroaryl group and A₅is H or alkyl. These compounds are said to be kinase inhibitors. Otherbenzimidazoles derivatives are known in the art. For example,WO2002/46168 A1 to AstraZeneca describes benzimidazoles derivatives thatare useful in the treatment or prophylaxis of Alzheimer's disease,anxiety disorders, depressive disorders, osteoporosis, cardiovasculardisease, rheumatoid arthritis or prostate cancer. US2007/0270420 A1 toVertex Pharmaceuticals describes benzimidazole compounds that are usefulof inhibitors of GSK-3 and Lck protein kineases. Other benzimidazolederivatives are described in US 2009/0018124 A1, WO2004/0862638,WO2008/073451 A1 and US 2005/0272756 A1.

Novartis in US 2010/0261698 A1 describes indole derivatives of theformula:

Novatis indicates that these compounds inhibit aldosterone synthase andmay be useful in the treatment of disease states such as heart failureand hypertension. In WO2010/130,796 A1 and WO2011/061168, Novartisdiscloses aryl-pyridine derivatives that are said to inhibit aldosteronesynthase.

US 2009/0221591 A1 to Universitat des Saarlandes also disclosescompounds that inhibit CYP11B1 and CYP11B2. WO 2009/135651 toUniversitat des Saarlandes teaches that compounds of the formula:

possess the ability to inhibit aldosterone synthase.

WO1999/400094 Bayer AG discloses oxazolidinones with azol-containingtricycles as having antibacterial activity.

U.S. Pat. No. 7,381,825 to Takeda describes histone deacetylaseinhibitors of the formula

Z-Q-L-M

where Q is a substituted or unsubstituted aromatic ring, L is asubstituent providing between 0-10 atoms separation between M and theremainder of the compound, M is a substituent capable of complexing witha deacetylase catalytic site and/or metal ion, and Z is list of bicyclicgroups, including but not limited to

where X is CR₁₂ or N. These compounds are said to be useful in treatingcell-proliferative diseases such as, for example, leukemia, melanoma,bladder cancer, etc.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides for novelimidazopyridyl compounds, which are inhibitors of CYP11B2, ormetabolites, stereoisomers, salts, solvates or polymorphs thereof,processes of preparing such compounds, pharmaceutical compositionscomprising one or more such compounds, processes of preparingpharmaceutical compositions comprising one or more such compounds andpotentially methods of treatment, inhibition or amelioration of one ormore disease states associated with inhibiting CYP11B2 by administeringan effective amount at least one of the inventive imidazopyridylcompounds to a patient in need thereof.

In one aspect, the present application discloses a compound or apharmaceutically acceptable salt, metabolite, solvate, prodrug orpolymorph of said compound, said compound having the general structureshown in Formula I

or a pharmaceutically acceptable salt thereof

wherein:

Ring A is attached to Ring B via positions D and E and is:

D is C;

E is N;

R¹ is H or alkyl;

R² is halogen; —CN; —OR⁷; —N(R¹⁰)C(O)R⁷; —NR¹¹R¹²; —C(O)R⁷;—C(O)N(R¹¹)(R¹²); —C(O)OR⁷; —S(O)_(m)—R⁷; alkyl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, —OR⁷, NR⁸R⁹, CN,N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times (e.g., 1 to 4 times)by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;

R³ is H; halogen; —CN; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen or cycloalkyl optionally substitutedonce or twice by alkyl or halogen; cycloalkyl optionally substitutedonce or twice by alkyl or halogen; or —C(O)OR⁷;

R⁴ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷; —C(O)OR⁷;—C(O)N(R⁸)(R⁹); —C(O)OR⁷; —N(R¹⁰)S(O)₂—OR⁷; or —S(O)_(m)—OR⁷; alkyloptionally substituted one or more times (e.g., 1 to 4 times) byhalogen, —OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—N(R¹⁰)S(O)₂—R⁷ or —S(O)_(n)R⁷; cycloalkyl optionally substituted one ormore times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times (e.g., 1 to 4 times) byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷,—CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;

R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷; —C(O)N(R⁸)(R⁹);—C(O)R⁷; —C(O)OR⁷; —N(R¹⁰)S(O)₂—OR⁷; —S(O)_(n)—R⁷; alkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, —OR⁷,—NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —N(R¹⁰)S(O)₂—R⁷,or —S(O)—R⁷; cycloalkyl optionally substituted one or more times (e.g.,1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; aryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one ormore times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷,—CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;

-   -   or R⁴ and R⁵ are joined together to form a 5- to 7-membered        carbocyclic or heterocyclic ring that is fused to the pyridyl        ring to which R⁴ and R⁵ are attached, wherein the ring formed by        R⁴ and R⁵ is optionally substituted by 1 to 3 R⁶;

R⁶ is independently H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷;—C(O)N(R⁷)(R⁸); —C(O)N(R⁸)(R⁹); —C(O)OR⁷; —S(O)_(m)—R⁷; alkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, —OR⁷,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;cycloalkyl optionally substituted one or more times (e.g., 1 to 4 times)by halogen, alkyl, haloalkyl, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; aryl optionally substitutedone or more times (e.g., 1 to 4 times) by halogen, alkyl, haloalkyl,cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times (e.g., 1 to 4 times)by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;

R⁷ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; aryl optionally substituted one or more times (e.g., 1to 4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰;or heteroaryl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN,—N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰;

R⁸ is independently H or alkyl;

R⁹ is independently H or alkyl;

-   -   or R⁸ and R⁹ are joined together with the nitrogen to which they        are attached form a saturated 5- to 7-membered heterocyclic        ring;

R¹⁰ is independently H or alkyl;

R¹¹ is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷;

R¹² is independently H; alkyl optionally substituted one or more times(e.g., 1 to 4 times) by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times (e.g., 1 to4 times) by halogen, alkyl, haloalkyl, cycloalkyl, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times (e.g., 1 to 4times) by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times (e.g., 1 to 4 times) by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷;

a is 0, 1, 2, 3, or 4 (e.g., 0, 1 or 2);

n is 1 or 2; and

m is 0, 1 or 2.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

Another aspect of the present invention is pharmaceutical compositionscomprising a therapeutically effective amount of at least one compoundof Formula I or a pharmaceutically acceptable salt thereof, atherapeutically effective amount of at least one additional therapeuticagent and a pharmaceutically acceptable carrier.

Another aspect of the present invention potentially is the prevention ofone or more disease states associated associated with inhibiting CYP11B2by administering an effective amount at least one of the inventiveimidazopyridyl compounds to a patient in need thereof.

It is further contemplated that the combination of the invention couldbe provided as a kit comprising in a single package at least onecompound of Formula I or a pharmaceutically acceptable salt thereof in apharmaceutical composition, and at least one separate pharmaceuticalcomposition, such as, for example a separate pharmaceutical compositioncomprising a therapeutic agent.

The compounds of the present invention could be useful in the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2 by administering a therapeutically effective amountof at least one compound of Formula I or a pharmaceutically acceptablesalt thereof to a mammal in need of such treatment. Conditions thatcould be treated or prevented by inhibiting CYP11B2 includehypertension, heart failure such as congestive heart failure, diastolicdysfunction, left ventricular diastolic dysfunction, heart failure(including congestive heart failure), diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, systolicdysfunction, hypokalemia, renal failure (including chronic renalfailure), restenosis, syndrome X, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,vascular diseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, myocardial infarction, left ventricularhypertrophy, cardiac lesions, vascular wall hypertrophy, endothelialthickening or fibrinoid necrosis of coronary arteries.

The compounds of the present invention also might be useful in treatingone or more conditions characterized by increased stress hormone levelsand/or decreased androgen hormone levels in a mammal by administering atherapeutically effective amount of at least one compound of Formula Ior a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment. Conditions characterized by increased stress hormonelevels and/or decreased androgen hormone levels in a mammal include, forexample, heart failure (e.g., acute heart failure, acute decompensatedheart failure, chronic heart failure, chronic heart failure withimpaired exercise tolerance or chromic heart failure with muscleweakness), cachexia (e.g., cardiac cachexia, COPD-induced cachexia,cirrhosis-induced cachexia, tumor-induced cachexia or viral(HIV)-induced cachexia), acute coronary syndrome, Cushing's syndrome ormetabolic syndrome.

Another aspect of the present invention is the use of a compound ofFormula I or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment, amelioration orprevention of one or more conditions associated with inhibiting CYP11B2in a patient.

This invention further relates to process for the preparation of thecompounds of Formula I or their pharmaceutically acceptable salts.Moreover, this invention also relates to the use of the compounds ofFormula I or their pharmaceutically acceptable salts to validate invitro assays, such as, for example the V79-Human-CYP11B2 andV79-Human-CYP11B1 discussed later in the application.

These and other objectives will be evident from the description of theinvention contained herein.

DETAILED DESCRIPTION

In an embodiment, the present invention provides compounds representedby structural Formula I or pharmaceutically acceptable salt thereof,wherein the various moieties are as described as above.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula II

wherein R², R³, R⁴, R⁵ and a are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula III

wherein R¹, R³, R⁴, R⁵ and a are as defined in Formula I.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula IV

wherein R², R³ and a are as defined in Formula I and b is 0, 1 or 2(e.g, where b is 0, or where b is 1 or 2 and R⁶ is alkyl or halo).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of Formula I represented by structuralFormula V

wherein R¹, R² and a are as defined in Formula I and b is 0, 1 or 2(e.g, where b is 0, or where b is 1 or 2 and R⁶ is alkyl or halo).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through V, a is 0 or a is 1 or 2 and R² is independently halogen(e.g., F or Cl), —CN, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl), —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), or haloalkyl (e.g., —CF₃)), haloalkyl (e.g., —CF₃),cycloalkyl (e.g., cyclopropyl or cyclohexyl) or phenyl optionallysubstituted by halogen.

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any the embodiments of Formulae Ithrough V described above where R³ is H, halogen, —CN, alkyl (e.g.,methyl, ethyl, n-propyl, propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), or cycloalkyl (e.g., cyclopropyl or cyclohexyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁴ is H, halogen (e.g., —F or Cl), —CN, alkyl(e.g., methyl or ethyl) or cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁴ is H or alkyl (e.g., methyl or ethyl).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts of any of the embodiments of FormulaeI through III above where R⁵ is H, halogen (e.g., —F or Cl), —CN, alkyl(e.g., methyl, ethyl, n-propyl, propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl), —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl) or haloalkyl (e.g.,—CF₃)), haloalkyl (e.g., —CF₃) or phenyl optionally substituted byhalogen, —OR⁷ (where R⁷ is H, alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl)) or haloalkyl(e.g., —CF₃).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through III described above where R⁴ is H and R⁵ is H, halogen(e.g., —F or CO, —CN, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl), —OR⁷ (where R⁷ is H, alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl) or haloalkyl (e.g., —CF₃)), haloalkyl (e.g., —CF₃) or phenyloptionally substituted by halogen, —OR⁷ (where R⁷ is H, alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl) or haloalkyl (e.g., —CF₃)).

Another embodiment of the present invention is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormulae I through III described above where R⁵ is C(O)OR⁷ (e.g., R⁷ isC₁-C₄-alkyl or phenyl, optionally substititued by halogen or haloalkyl).

Another embodiment of the present inventions is compounds or theirpharmaceutically acceptable salts thereof of any of the embodiments ofFormula I through III described above or their pharmaceuticallyacceptable salts thereof where R⁴ is H and R⁵ is a group of the formula:

where:

-   -   R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to        3 —F (e.g. CF₃);    -   R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1        to 3 —F (e.g. CF₃);    -   R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3 —F        (e.g. —CF₃), is —OC₁-C₃-alkyl, —N(H)S(O)₂—C₁-C₃-alkyl,        optionally substituted with 1 to 3 —F (e.g. —CF₃),        —N(H)C(O)C₁-C₃-alkyl, optionally substituted with 1 to 3 —F        (e.g. —CF₃).

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Mammal” means humans and other mammalian animals.

The following definitions apply regardless of whether a term is used byitself or in combination with other terms, unless otherwise indicated.Therefore, the definition of “alkyl” applies to “alkyl” as well as the“alkyl” portions of “hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched.

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Examples are fluoro, chloro or bromo.

“Halogen” means fluorine, chlorine, bromine, or iodine.

“Haloalkyl” means a halo-alkyl-group in which the alkyl group is aspreviously described. The bond to the parent moiety is through thealkyl. Non-limiting examples of suitable haloalkyl groups includefluoromethyl, difluoromethyl, —CH₂CF₃, —CH₂CHF₂—CH₂CH₂F, or an alkylgroup with one or more terminal carbons tri-substituted with a halogen(e.g., —F) such as, for example —C₁-C₃alkyl-CF₃, —CH(CH₃)(CF₃),—CH(CF₃)₂ and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, aswell as partially saturated species such as, for example, indanyl,tetrahydronaphthyl and the like.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. Non-limiting examples of suitable aryl groups includephenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

“Heterocycloalkyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocycloalkyl root name means thatat least a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocycloalkyl ring may exist protected suchas, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like;such protections are also considered part of this invention. Thenitrogen or sulfur atom of the heterocycloalkyl ring can be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.Non-limiting examples of suitable monocyclic heterocycloalkyl ringsinclude piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiopyranyl, oxetanyl,tetrahydrothiophenyl, lactam, lactone, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination, provided that the rings do not include adjacent oxygenand/or sulfur atoms. N-oxides of the ring nitrogens are also included,as well as compounds wherein a ring nitrogen is substituted by an alkylgroup to form a quaternary amine. Preferred heteroaryls contain about 5to about 6 ring atoms. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl,tetrazolyl, pyrimidyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, naphthyridyl (e.g., 1,5 or 1,7), pyrido[2,3]imidazolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, pyridopyrimidinyl,7-azaindolyl and the like. The term “heteroaryl” also refers topartially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. All positionalisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.

It should be noted that in heterocycloalkyl ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

When R⁴ and R⁵ are joined together to form a 5-7 membered carbocyclicring that is fused to the pyridyl ring to which R⁴ and R⁵ are attached,“carbocyclic” means a cycloalkyl, aryl or partially unsaturated ringcomposed of 5-7 carbon atoms wherein two of the carbons are sharedbetween the fused rings. When R⁴ and R⁵ are joined together to form a5-7 membered heterocyclic ring that is fused to the pyridyl ring towhich R⁴ and R⁵ are attached, “heterocyclic” means a fully saturated,partially saturated or aromatic ring composed of carbon atoms and one,two or three heteroatoms selected from N, S, or O, wherein two of thecarbons are shared between the fused rings. Representative ring include:

When a moiety can be optionally substituted, it means that each carbonand heteroatom (when present) available for substitution in the givenmoiety may be independently unsubstituted or substituted with specifiednumber of substituents that are the same or different at each occurrenceand which result in the creation of a stable structure as is understoodto be reasonable by one skilled in the art.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond, such as R² in structuralFormula III are permitted on any available carbon atom in the ring towhich each is attached.

When R⁸ and R⁹ together with the nitrogen to which they are attachedform a saturated 5- to 7-membered heterocyclic ring, this means asaturated heterocyclic ring composed of, in addition to the one nitrogenatom, carbon atoms and optionally one additional heteroatom selectedfrom N, S or O. Representative examples include:

The present invention encompasses all stereoisomeric forms of thecompounds of Formula I. Centers of asymmetry that are present in thecompounds of Formula I can all independently of one another have (R)configuration or (S) configuration. When bonds to the chiral carbon aredepicted as straight lines in the structural Formulas of the invention,it is understood that both the (R) and (S) configurations of the chiralcarbon, and hence both enantiomers and mixtures thereof, are embracedwithin the Formula. Similarly, when a compound name is recited without achiral designation for a chiral carbon, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. Theproduction of specific stereoisomers or mixtures thereof may beidentified in the Examples where such stereoisomers or mixtures wereobtained, but this in no way limits the inclusion of all stereoisomersand mixtures thereof from being within the scope of this invention.

The invention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, enantiomers are asubject of the invention in enantiomerically pure form, both aslevorotatory and as dextrorotatory antipodes, in the form of racematesand in the form of mixtures of the two enantiomers in all ratios. In thecase of a cis/trans isomerism the invention includes both the cis formand the trans form as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, if desired,by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Where compounds of thisinvention are capable of tautomerization, all individual tautomers aswell as mixtures thereof are included in the scope of this invention.The present invention includes all such isomers, as well as salts,solvates (including hydrates) and solvated salts of such racemates,enantiomers, diastereomers and tautomers and mixtures thereof.

Reference to the compounds of this invention as those of a specificformula or embodiment, e.g., Formula I (which includes the compounds ofFormulae II-V all embodiments herein) or any other generic structuralformula or specific compound described or claimed herein, is intended toencompass the specific compound or compounds falling within the scope ofthe formula or embodiment, including salts thereof, particularlypharmaceutically acceptable salts, solvates of such compounds andsolvated salt forms thereof, where such forms are possible unlessspecified otherwise.

In the compounds of Formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formula I. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin Formula Ia can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

When the compounds of Formula I contain one or more acidic or basicgroups the invention also includes the corresponding physiologically ortoxicologically acceptable salts, in particular the pharmaceuticallyutilizable salts. Thus, the compounds of Formula I which contain acidicgroups can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Examplesof such salts include but are not limited to sodium salts, potassiumsalts, calcium salts, magnesium salts or salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of Formula I which contain one or more basicgroups, i.e. groups which can be protonated, can be used according tothe invention in the form of their acid addition salts with inorganic ororganic acids as, for example but not limited to, salts with hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroaceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofFormula I simultaneously contain acidic and basic groups in the moleculethe invention also includes, in addition to the salt forms mentioned,inner salts or betaines (zwitterions). Salts can be obtained from thecompounds of Formula I by customary methods which are known to theperson skilled in the art, for example by combination with an organic orinorganic acid or base in a solvent or dispersant, or by anion exchangeor cation exchange from other salts. The present invention also includesall salts of the compounds of Formula I which, owing to lowphysiological compatibility, are not directly suitable for use inpharmaceuticals but which can be used, for example, as intermediates forchemical reactions or for the preparation of physiologically (i.e.,pharmaceutically) acceptable salts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I areintended to be included within the scope of the present invention. Inaddition, some of the compounds of the instant invention may formsolvates with water (i.e., a hydrate) or common organic solvents. Suchsolvates and hydrates, particularly the pharmaceutically acceptablesolvates and hydrates, of the instant compounds are likewise encompassedwithin the scope of this invention, along with un-solvated and anhydrousforms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid group or by formation of an ester on anavailable hydroxy group in a compound. Similarly, labile amides can bemade. Pharmaceutically acceptable esters or amides of the compounds ofthis invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO⁻ depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.

Examples of pharmaceutically acceptable pro-drug modifications include,but are not limited to, —C₁₋₆alkyl esters and —C₁₋₆alkyl substitutedwith phenyl esters.

Accordingly, the compounds within the generic structural formulas,embodiments and specific compounds described and claimed hereinencompass salts, all possible stereoisomers and tautomers, physicalforms (e.g., amorphous and crystalline forms), solvate and hydrate formsthereof and any combination of these forms, as well as the saltsthereof, pro-drug forms thereof, and salts of pro-drug forms thereof,where such forms are possible unless specified otherwise.

Compounds of the present invention are effective at inhibiting thesynthesis of aldosterone by inhibiting CYP11B2 (aldosterone synthase)and therefore might be useful agents for the therapy and prophylaxis ofdisorders that are associated with elevated aldosterone levels.Accordingly, an object of the instant invention is to provide a methodfor inhibiting aldosterone synthase, and more particularly selectivelyinhibiting CYP11B2, in a patient in need thereof, comprisingadministering a compound of Formula I to the patient in an amounteffective to inhibit aldosterone synthesis, or more particularly toselectively inhibit CYP11B2, in the patient. A selective inhibitor ofCYP11B2 is intended to mean a compound that preferentially inhibitsCYP11B2 as compared to CYP11B1. The inhibition of CYP11B2, as wellinhibition of CYP11B1, by the compounds of Formula I can be examined,for example, in the inhibition assays described below.

In general, compounds that have activity as aldosterone synthaseinhibitors can be identified as those compounds which have an IC₅₀ ofless than or equal to about 10 μM; preferably less than or equal toabout 250 nM; and most preferably less than or equal to about 100 nM, inthe V79-Human-CYP11B2 Assay described below. In general, aldosteronesynthase inhibitors that are selective for inhibition of CYP11B2 ascompared to CYP11B1 are those that show at least 3-fold greaterinhibition for CYP11B2 compared to CYP11B1; preferably at least 20-foldinhibition for CYP11B2 compared to CYP11B1; and more preferably at least100-fold greater inhibition for CYP11B2 compared to CYP11B1, in theV79-Human-CYP11B2 Assay as compared to the V79-Human-CYP11B1 Assay.

Due to their ability to inhibit CYP11B2, the compounds of the presentinvention might be useful to treat and/or ameliorate the risk forhypertension, hypokalemia, renal failure (e.g., chromic renal failure),restenosis, Syndrome X, nephropathy, post-myocardial infarction,coronary heart diseases, increased formation of collagen, fibrosis andremodeling following hypertension and endothelial dysfunction,cardiovascular diseases, renal dysfunction, liver diseases, vasculardiseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, heart failure (e.g., congestiveheart failure), diastolic heart failure, left ventricle diastolicdysfunction, diastolic heart failure, systolic dysfunction, ischemia,myocardial and vascular fibrosis, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, cardiaclesions, vascular wall hypertrophy, endothelial thickening or necrosisof coronary arteries.

The dosage amount of the compound to be administered depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof Formula I. A consideration of these factors is well within thepurview of the ordinarily skilled clinician for the purpose ofdetermining the therapeutically effective or prophylactically effectivedosage amount needed to prevent, counter, or arrest the progress of thecondition. It is expected that the compound will be administeredchronically on a daily basis for a length of time appropriate to treator prevent the medical condition relevant to the patient, including acourse of therapy lasting days, months, years or the life of thepatient.

In general, a daily dose of approximately 0.001 to 30 mg/kg, preferably0.001 to 20 mg/kg, in particular 0.01 to 10 mg/kg (in each case mg perkg of bodyweight) is appropriate for administration to an adult weighingapproximately 75 kg in order to obtain the desired results. The dailydose is preferably administered in a single dose or, in particular whenlarger amounts are administered, can be divided into several, forexample two, three or four individual doses, and may be, for example,but not limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, etc.,on a daily basis. In some cases, depending on the individual response,it may be necessary to deviate upwards or downwards from the given dailydose.

The term “patient” includes animals, preferably mammals and especiallyhumans, who use the instant active agents for the prevention ortreatment of a medical condition. Administering of the drug to thepatient includes both self-administration and administration to thepatient by another person. The patient may be in need of treatment foran existing disease or medical condition, or may desire prophylactictreatment to prevent or reduce the risk of said disease or medicalcondition.

The term therapeutically effective amount is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.A prophylactically effective amount is intended to mean that amount of apharmaceutical drug that will prevent or reduce the risk of occurrenceof the biological or medical event that is sought to be prevented in atissue, a system, animal or human by a researcher, veterinarian, medicaldoctor or other clinician. The terms “preventing” or “prevention” asused herein referx to administering a compound before the onset ofclinical symptoms.

It is understood that a specific daily dosage amount can simultaneouslybe both a therapeutically effective amount, e.g., for treatment ofhypertension, and a prophylactically effective amount, e.g., forprevention of myocardial infarction.

In the methods of treatment of this invention, the compound may beadministered via any suitable route of administration such as, forexample, orally, parenterally, or rectally in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Oral formulations are preferred,particularly solid oral dosage units such as pills, tablets or capsules.

Accordingly, this invention also provides pharmaceutical compositionscomprised of a compound of Formula I and a pharmaceutically acceptablecarrier. For oral use, the pharmaceutical compositions of this inventioncontaining the active ingredient may be in forms such as pills, tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients, which are suitable for the manufacture oftablets. These excipients may be for example, inert diluents, such ascalcium carbonate, sodium carbonate, lactose, mannitol, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. Pharmaceutical compositionsmay also contain other customary additives, for example, wetting agents,stabilizers, emulsifiers, dispersants, preservatives, sweeteners,colorants, flavorings, aromatizers, thickeners, diluents, buffersubstances, solvents, solubilizers, agents for achieving a depot effect,salts for altering the osmotic pressure, coating agents or antioxidants.

Oral immediate-release and time-controlled release dosage forms may beemployed, as well as enterically coated oral dosage forms. Tablets maybe uncoated or they may be coated by known techniques for aestheticpurposes, to mask taste or for other reasons. Coatings can also be usedto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Oilysuspensions may be formulated by suspending the active ingredient in avegetable oil, for example arachis oil, olive oil, sesame oil or coconutoil, or in mineral oil such as liquid paraffin. The oily suspensions maycontain a thickening agent, for example beeswax, hard paraffin or cetylalcohol. Sweetening agents and flavoring agents may be added to providea palatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid. Syrups and elixirsmay be formulated with sweetening agents, for example glycerol,propylene glycol, sorbitol or sucrose.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining a compound of Formula Iwith a pharmaceutically acceptable carrier. Also encompassed is thepharmaceutical composition which is made by combining a compound ofFormula I with a pharmaceutically acceptable carrier. The carrier iscomprised of one or more pharmaceutically acceptable excipients.Furthermore, a therapeutically effective amount of a compound of thisinvention can be used for the preparation of a medicament useful forinhibiting aldosterone synthase, inhibiting CYP11B2, for normalizing adisturbed aldosterone balance, or for treating or preventing any of themedical conditions described herein, in dosage amounts described herein.

The amount of active compound of Formula I and its pharmaceuticallyacceptable salts in the pharmaceutical composition may be, for examplebut not limited to, from 0.1 to 200 mg, preferably from 0.1 to 50 mg,per dose on a free acid/free base weight basis, but depending on thetype of the pharmaceutical composition and potency of the activeingredient it could also be lower or higher. Pharmaceutical compositionsusually comprise 0.5 to 90 percent by weight of the active compound on afree acid/free base weight basis.

Since the compounds of Formula I inhibit aldosterone synthase, apartfrom use as pharmaceutically active compounds in human medicine andveterinary medicine, they can also be employed as a scientific tool oras aid for biochemical investigations in which such an effect onaldosterone synthase and aldosterone levels is intended, and also fordiagnostic purposes, for example in the in vitro diagnosis of cellsamples or tissue samples. The compounds of Formula I can also beemployed as intermediates for the preparation of other pharmaceuticallyactive compounds.

One or more additional pharmacologically active agents (or therapeuticagents) may be administered in combination with a compound of Formula I.An additional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) different from the compound ofFormula I. Generally, any suitable additional active agent or agents,including but not limited to anti-hypertensive agents,anti-atherosclerotic agents such as a lipid modifying compound,anti-diabetic agents and/or anti-obesity agents may be used in anycombination with the compound of Formula I in a single dosageformulation (a fixed dose drug combination), or may be administered tothe patient in one or more separate dosage formulations which allows forconcurrent or sequential administration of the active agents(co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to angiotensin converting enzyme (ACE) inhibitors (e.g,alacepril, benazepril, captopril, ceronapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexepril,moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril); dual inhibitors of angiotensin converting enzyme (ACE)and neutral endopeptidase (NEP) such as omapatrilat, sampatrilat andfasidotril; angiotensin II receptor antagonists (e.g., candesartan,eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan)neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon),aldosterone antagonists, renin inhibitors (e.g., enalkrein, RO 42-5892,A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, vasodilators, calcium channel blockers (e.g., amlodipine,bepridil, diltiazem, felodipine, gallopamil, nicardipine, nifedipine,niludipine, nimodipine, nisoldipine veraparmil), potassium channelactivators (e.g., nicorandil, pinacidil, cromakalim, minoxidil,aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide) includingloop diuretics such as ethacrynic acid, furosemide, bumetanide andtorsemide, sympatholitics, beta-adrenergic blocking drugs (e.g.,acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol,metoprolol tartate, nadolol, propranolol, sotalol, timolol); alphaadrenergic blocking drugs (e.g., doxazocin, prazocin or alphamethyldopa) central alpha adrenergic agonists, peripheral vasodilators(e.g. hydralazine); lipid lowering agents (e.g., simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®),and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium); niacin inimmediate-release or controlled release forms, and particularly inniacin in combination with a DP antagonist such as laropiprant(TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacinreceptor agonists such as acipimox and acifran, as well as niacinreceptor partial agonists; metabolic altering agents including insulinsensitizing agents and related compounds (e.g., muraglitazar, glipizide,metformin, rosiglitazone), dipeptidyl peptidase 4 inhibitors (e.g.,sitagliptin, alogliptin, vildagliptin, saxagliptin, linagliptin,dutogliptin, gemigliptin); or with other drugs beneficial for theprevention or the treatment of the above-mentioned diseases includingnitroprusside and diazoxide.

In general, the compounds in the invention may be produced by a varietyof processes know to those skilled in the art and by know processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods and one skilled in the artwould have resources such as Chemical Abstracts or Beilstein at his orher disposal to assist in devising an alternative method of preparing aspecific compound.

The compounds of the present invention can be prepared according to theprocedures of the following Schemes using appropriate materials and arefurther exemplified by the specific Examples which follow. Moreover, byutilizing the procedures described herein, one of ordinary skill in theart can readily prepare additional compounds of the present inventionclaimed herein.

Throughout the synthetic schemes, abbreviations are used with thefollowing meanings unless otherwise indicated:

AcCN=acetonitrile; aq=aqueous, Ar=aryl; BSA=bovine serum albumin;Bu=butyl, t-Bu=tert-butyl; n-BuLi=n-butyllithium; conc,conc.=concentrated; c-Pr=cyclopropyl; Cy=cyclohexyl;dba=dibenzylideneacetone; DCM=dichloromethane; DMEM=Dulbecco's modifiedeagle medium; DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;eq.=equivalent(s); EDAC=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride; EDTA=ethylenediaminetetraacetic acid; Et=ethyl;EtOAc=ethyl acetate; EtOH=ethanol; FBS=Fetal Bovine Serum; h, hr=hour;HPLC=High pressure liquid chromatography; HTRF=homogenous time resolvedfluorescence; i-PrOH=isopropanol; i-Pr=isopropyl; LCMS=liquidchromatography-mass spectroscopy; Me=methyl; MeOH=methanol; min,min.=minute; MS=mass spectroscopy; NBS=N-bromosuccinimide;NCS=N-chlorosuccinimide; NMR=nuclear magnetic resonance; PBS=phosphatebuffered saline; PdCl₂(dppf)=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II);Pd₂(dba)₃=tris(dibenzylidineacetone)dipalladium; Pd/C=palladium onactivated carbon; Ph=phenyl; Pr=propyl; Py=pyridyl;PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; OAc=acetate; OTf=trifluoromethanesulfonate; RT,rt=room temperature; sat.=saturated;S-Phos=2-dichlorocyclohexylphosphino-2′,6′-dimethoxybiphenyl;TBAF=tetrabutylammonium fluoride; TBDMS=tert-butyldimethylsilyl;THF=tetrahydrofuran; triflate, and TfO₂=trifluoromethanesulfonicanhydride.

As will be known to those skilled in the art, in all schemes, theproducts of Formula I and all synthetic intermediates may be purifiedfrom unwanted side products, reagents and solvents by recrystallization,trituration, preparative thin layer chromatography, flash chromatographyon silica gel as described by W. C. Still et al, J. Org. Chem. 1978, 43,2923, or reverse-phase HPLC. Compounds purified by HPLC may be isolatedas the corresponding salt.

Additionally, in some instances the final compounds of Formula I andsynthetic intermediates may be comprised of a mixture of cis and transisomers, enantiomers or diastereomers. As will be known to those skilledin the art, such cis and trans isomers, enantiomers and diastereomersmay be separated by various methods including crystallization,chomatography using a homochiral stationary phase and, in the case ofcis/trans isomers and diastereomers, normal-phase and reverse-phasechromatography.

Chemical reactions were monitored by LCMS, and the purity and identityof the reaction products were assayed by LCMS (electrospray ionization)and NMR. LCMS spectra were recorded on an Agilent 1100 series instrumentequipped with an Xterra MS C18 column (3.5 μM, 3.0×50 mm i.d.) and UVdetector. ¹H NMR spectra were recorded on a Varian 500 HHz spectrometerunless otherwise noted, and are internally referenced to residual protiosolvent signals. Data for ¹H NMR are reported with chemical shift (8ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, br s=broad singlet, br m=broad multiplet), couplingconstant (Hz), and integration. Unless otherwise noted, all LCMS ionslisted are [M+H]. All temperatures are degrees Celsius unless otherwisenoted.

In the Examples, some intermediates and final compounds having a chiralcarbon were prepared as racemates, and some chiral intermediates wereresolved and the enantiomers were used separately to synthesizeenantiomeric downstream intermediates and final products. In some casesracemic final products may have been resolved. In the instances wherechiral compounds were separated by chiral HPLC purification, the term“enantiomer A” or “ent A” refers to the first eluting enantiomer and thedownstream compounds derived from this enantiomer. The term “enantiomerB” or “ent B” refers to the second eluting enantiomer and the downstreamcompounds derived from this enantiomer. The term “rac” refers to aracemic mixture. As a result, the chemical nomenclature may indicatethat an S and/or an R enantiomer was obtained, but the absolutestereochemistry of the separate enantiomers A and/or B was notdetermined.

Preparative HPLC was performed using a SunFire Prep C 18 OBD column (5μM, 19×100 mm i.d.) on Gilson instruments equipped with UV detectors.

Flash chromatography on silica gel was performed using pre-packed silicagel columns on Biotage Horizon or Biotage SP-1 instruments equipped withUV detectors.

The following examples are provided so that the invention might be morefully understood. They should neither be construed as forming the onlygenus that is considered as the invention nor limiting the invention inany way.

2-Heteroaryl imidazo[1,2-a]pyridines can be synthesized according to theprocedure outlined in Scheme 1. 2-Aminopyridines such as 1 are availablecommercially, are known in the literature or may be synthesized by avariety of procedures by those skilled in the art. Upon heating in thepresence of a dehydrating agent such as TiCl₄, and a base such astriethylamine, 2-aminopyridines 1 may undergo cyclization with3-bromoacetylpyridines such as 2 to afford 2-heteroarylimidazo[1,2-a]pyridines such as 3.

2-Heteroaryl imidazo[1,2-a]pyridines can alternatively be synthesizedaccording by the method outlined in Scheme 2. 2-Aminopyridine 1 may betreated with ethyl bromoacetate to afford 2-imino pyridyl acetic acidester 4, which may then be converted to 2-chloro imidazo[1,2-a]pyridine5 upon heating in the presence of an activating agent such asoxyphosphorous chloride. Treatment of 3 with an iodinating agent such asN-iodosuccinimide may then afford 2-chloro-3-iodo imidazo[1,2-a]pyridine6. Boronate acids and esters may be obtained commercially, are known inthe literature or may be prepared by a variety of methods by thoseskilled in the art. Suzuki coupling of iodide 6 with a boronic acid orester in the presence of a catalyst such as palladium acetate, a ligandsuch as triphenylphosphine, and a base such as cesium carbonate atelevated temperature may afford coupled product 7. A subsequent Suzukicoupling between 7 and a heteroaryl boronic acid or ester in thepresence of a catalyst such as palladium acetate, a ligand such as2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, and a base suchas potassium phosphate tribasic may then afford 2-heteroarylimidazo[1,2-a]pyridine compound 8.

2-(Pyridin-3-yl)-5,6-dihydroimidazo[1,2-c]pyrimidin-7(8H)-ones 17 can besynthesized according to the method shown in Scheme 3. 4-Substitutedimidazole 9 may be treated with a base such as sodium hydride followedby an electrophile such as a tert-butylsilyldimethylsilyl-protectedbromoalkane to afford the alkylated imidazole 10 and its regioisomer.The correct regioisomer 10 may be brominated with a reagent such as N-bromosuccinimide to give the bromoimidazole 11, which upon Suzuki couplingwith a boronic acid or ester can then yield imidazolylpyridine 12.Subsequent bromination with N-bromosuccinimide, followed by aminationwith an amine in the presence of silver triflate can then afford theimidazolylpyridine 14. Deprotection of 14 with a reagent such astetrabutylammonium fluoride affords the alcohol 15. Oxidation of 15 withan appropriate oxidizing system, such as ruthenium chloride/sodiumperiodate, may afford the carboxylic acid 16, and with the addition ofthe coupling reagent EDAC, 16 may be converted to the desired2-(pyridin-3-yl)-5,6-dihydroimidazo[1,2-c]pyrimidin-7(8H)-ones 17.

Pyridyl boronate esters may be obtained commercially, are known in theliterature or may be prepared by a variety of methods by those skilledin the art. One such method, shown in Scheme 4, begins with treatment of3,5-dibromopyridine 18 with n-butyllithium and acetone in a solvent suchas toluene at low temperature to provide 19. Heating of bromide 19 and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in thepresence of a catalyst such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and a basesuch as potassium acetate in a solvent such as 1,4-dioxane then affordsboronate ester 20.

An alternative method for the preparation of pyridyl boronic acids,shown in Scheme 5, begins with treatment of1-(5-bromopyridin-3-yl)ethanone 21 with (trifluoromethyl)trimethylsilaneand tetrabutylammonium fluoride in a solvent such as tetrahydrofuran toprovide 22. Heating of bromide 22 and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in thepresence of a catalyst such as tris(dibenzylideneacetone) dipalladium(0), a ligand such as tricyclohexylphosphine, and a base such aspotassium acetate in a solvent such as 1,4-dioxane then affords boronicacid 23.

As will be known to those skilled in the art, in all schemes, theproducts of Formula I and all synthetic intermediates may be purifiedfrom unwanted side products, reagents and solvents by recrystallisation,trituration, preparative TLC, flash chromatography on silica gel orreverse-phase HPLC. Compounds purified by HPLC may be isolated as thecorresponding salt.

Example 1

Step A. 6-Fluoro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine

2-Amino-5-fluoropyridine (0.048 g, 0.427 mmol), 3-bromoacetylpyridinehydrobromide (0.10 g, 0.356 mmol) and chloroform (3.56 mL) were added toa microwave vial. To the resulting solution were added a solution ofTiCl₄ in dichloromethane (1.0 M, 0.267 mL, 0.267 mmol) and triethylamine(0.030 mL, 0.214 mmol). The reaction was then heated in a microwave at110° C. for 30 minutes. The resulting mixture was poured into aqueoussodium hydroxide solution (1.0 N) and extracted with ethyl acetate. Theorganic extracts were combined, dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by flashchromatography on silica gel (50% to 100% ethyl acetate in hexanes)provided the title compound: LCMS m/z 214.09 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃) δ 9.13 (d, J=1.7 Hz, 1H), 8.59-8.58 (m, 1H), 8.29-8.28 (m, 1H),8.10 (t, J=2.9, 2.9 Hz, 1H), 7.95 (s, 1H), 7.63 (dd, J=9.9, 5.1 Hz, 1H),7.40 (dd, J=7.9, 5.0 Hz, 1H), 7.18-7.14 (m, 1H).

Example 2

Step A. Ethyl 2-(5-fluoro-2-iminopyridin-1(2H)-yl)acetate

To 2-amino-5-fluoro pyridine (2.0 g, 17.84 mmol) was added ethylbromoacetate (6.92 mL, 62.4 mmol). The resulting mixture was stirred atroom temperature for 18 hours, then filtered. The solids were collected,washed with dichloromethane, and dried under under reduced pressure toafford the title compound: LCMS m/z 199.00 [M+H]⁺; ¹H NMR (500 MHz,CD₃OD) δ 8.05 (s, 1H), 7.93-7.90 (m, 1H), 7.14-7.12 (m, 1H), 5.02 (s,2H), 4.25 (t, J=7.1 Hz, 2H), 1.27 (q, J=7.1 Hz, 3H).

Step B. 2-Chloro-6-fluoroimidazo[1,2-a]pyridine

A mixture of ethyl 2-imino-5-fluoro-1,2-dihydropyridine-1-yl-acetatehydrobromide (4.12 g, 14.76 mmol) in phosphorus oxychloride (68.8 mL,738 mmol) was heated at 105° C. for 2 hours. The mixture was then cooledto room temperature and concentrated under reduced pressure. To theresulting residue were added ice water and ammonium hydroxide until thepH of the solution was 8. The solution was then extracted withdichloromethane. The organic extracts were combined, dried over MgSO4,filtered and concentrated under reduced pressure. Purification by flashchromatography on silica gel (30% ethyl acetate in hexanes) provided thetitle compound: LCMS m/z 170.96 [M+H]⁺, 172.79 [M+2+H]⁺; ¹H NMR (500MHz, CDCl₃) δ 8.00 (s, 1H), 7.53-7.50 (m, 2H), 7.18-7.13 (m, 1H).

Step C. 2-(5-Bromopyridin-3-yl)propan-2-ol

To a cooled (−78° C.) solution of 3-acetyl-5-bromo pyridine (1.98 g,9.90 mmol) in tetrahydrofuran (33 mL) was added dropwise a solution ofmethyl magnesium bromide in diethyl ether (3.0 M, 6.60 mL, 19.8 mmol).The reaction was warmed to room temperature, and the resulting mixturewas stirred at room temperature overnight. The reaction was thenquenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether. The organic extracts were combined, washed withbrine, dried over magnesium sulfate, filtered and concentrated.Purification by flash chromatography on silica gel (0-60% ethyl acetatein hexanes) provided the title compound: LCMS m/z 217.83 [M+11]⁺; ¹H NMR(500 MHz, CDCl₃) δ 8.61 (s, 1H), 8.53 (s, 1H), 8.01 (d, J=1.9 Hz, 1H),2.38 (br s, 1H), 1.61 (6H).

Step D.2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]-2-propanol

To a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen were added a solution of the title compoundfrom Example 2 Step C (160 g, 395 mmol) in 1,4-dioxane (2000 mL),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(240 g, 498 mmol), potassium acetate (240 g, 1.63 mol), and PdCl₂(dppf)(30 g, 23 mmol). The resulting solution was stirred for 4 hours at 80°C. The reaction was then cooled to room temperature, filtered andconcentrated under reduced pressure. The residual solution was dilutedwith hexanes and filtered. HCl gas was bubbled through the filtrate. Theresulting mixture was filtered, and the solids diluted withdichloromethane, then concentrated under reduced pressure. The residuewas diluted with H₂O, and washed sequentially with diethyl ether,dichloromethane, and hexanes. The aqueous layer was adjusted to pH 7-8with saturated aqueous sodium carbonate solution, then extracted withdichlormethane. The organic extracts were combined, dried andconcentrated under vacuum to afford the title compound: ¹H NMR (400 MHz,CDCl₃): δ 8.83 (s, 1H), 8.19 (s, 1H), 1.62 (s, 6H), 1.36 (s, 12H).

Step E.2-(5-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol

To a solution of the title compound from Example 2 Step D (0.1855 g,0.704 mmol) and the title compound from Example 2 Step B (0.10 g, 0.586mmol) in tetrahydrofuran (5.86 mL) were added palladium acetate (0.013g, 0.059 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl(0.048 g, 0.117 mmol), and potassium phosphate tribasic (0.373 g, 1.759mmol). The resulting mixture was heated at 100° C. for 18 hours. Themixture was then cooled to room temperature, filtered with the aid ofethyl acetate, and concentrated under reduced pressure. Purification byflash chromatography on silica gel (30-50% acetone in dichloromethane)provided the title compound: LCMS m/z 273.99 [M+H]⁺; ¹H NMR (500 MHz,CDCl₃) δ 8.99 (d, J=1.6 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.39 (t, J=2.0Hz, 1H), 8.10 (t, J=2.6 Hz, 1H), 7.96 (s, 1H), 7.63 (dd, J=9.9, 4.8 Hz,1H), 7.17-7.13 (m, 1H), 2.00 (br s, 1H), 1.68 (s, 6H).

Step F.2-(5-(3-Chloro-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol

To a solution of the title compound from Example 2 Step E (0.068 g,0.251 mmol) in acetonitrile (1.25 ml) was added N-chlorosuccinimide(0.040 g, 0.301 mmol). The resulting mixture was stirred at roomtemperature for 2 hours, then concentrated under reduced pressure. Theresulting residue was diluted with dichloromethane, washed withsaturated aqueous sodium chloride solution, dried over MgSO₄, filtered,and concentrated under reduced pressure. Purification by flashchromatography on silica gel (100% ethyl acetate) provided the titlecompound: LCMS m/z 306.08 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) 9.23 (d, J=1.7Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.08 (t, J=2.5Hz, 1H), 7.65 (dd, J=9.3, 4.9 Hz, 1H), 7.24-7.20 (m, 1H), 2.02 (br s,1H), 1.69 (s, 6H).

Example 3

Step A. 2-Chloro-6-fluoro-3-iodoimidazo[1,2-a]pyridine

To a solution of the title compound from Example 2 Step B (1.0 g, 5.86mmol) in acetonitrile (29.3 mL) was added N-iodosuccinimide (1.583 g,7.04 mmol). The resulting mixture was stirred at room temperature for 2hours, then concentrated under reduced pressure. The resulting residuewas diluted with dichloromethane, washed with saturated aqueous sodiumchloride solution, dried over MgSO₄, filtered, and concentrated underreduced pressure. Purification by flash chromatography on silica gel(10-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z296.70 [M+H]⁺, 298.65 [M+2+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.03 (t, J=2.8Hz, 1H), 7.56-7.51 (m, 1H), 7.22-7.18 (m, 1H).

Step B. 2-Chloro-6-fluoro-3-methylimidazo[1,2-a]pyridine

A mixture of the title compound from Example 3 Step A (0.500 g, 1.69mmol), palladium acetate (0.038 g, 0.169 mmol), methyl boronic acid(0.202 g, 3.37 mmol), cesium carbonate (1.65 g, 5.06 mmol) and triphenylphosphine (0.088 g, 0.337 mmol) in tetrahydrofuran (8.43 mL) was heatedin a sealed tube at 100° C. for 18 hours. The mixture was then cooled toroom temperature, filtered, and concentrated under reduced pressure.Purification by flash chromatography on silica gel (0-20% ethyl acetatein hexanes) provided the title compound: LCMS m/z 184.9 [M+H]⁺ 186.86[M+2+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J=2.4 Hz, 1H), 7.51 (dd,J=9.7, 4.9 Hz, 1H), 7.14-7.102 (m, 1H), 2.44 (s, 3H).

Step C.2-(5-(6-Fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol

To a solution of the title compound from Example 2 Step D (0.135 g,0.514 mmol) and the title compound from Example 3 Step B (0.079 g, 0.428mmol) in tetrahydrofuran (4.28 mL) were added palladium acetate (9.61mg, 0.043 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl(0.035 g, 0.086 mmol), and potassium phosphate tribasic (0.273 g, 1.284mmol). The resulting mixture was heated at 100° C. for 18 hours, thenfiltered with the aid of ethyl acetate and concentrated under reducedpressure. Purification by flash chromatography on silica gel (50%acetone in dichloromethane) provided the title compound: LCMS m/z 286.17[M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.26 (d,J=2.0 Hz, 1H), 7.85 (s, 1H), 7.63 (dd, J=9.8, 5.1 Hz, 1H), 7.16-7.12 (m,1H), 2.64 (s, 3H), 2.28 (br s, 1H), 1.67 (s, 6H).

Example 4

Step A. 2-Chloro-6-fluoroimidazo[1,2-a]pyridine-3-carbonitrile

To a cooled −78° C. solution of the title compound from Example 3 Step A(0.30 g, 1.01 mmol) in tetrahydrofuran (5.06 ml) was added a solution ofn-butyllithium in hexanes (1.6 M, 0.696 ml, 1.11 mmol). After 5 minutes,p-toluenesulfonyl cyanide (0.238 g, 1.32 mmol) was addd, and theresulting mixture was allowed to slowly warm to room temperatureovernight. The resulting mixture was concentrated under reduced pressureand purified by flash chromatography on silica gel (10-50% ethyl acetatein hexanes) to afford the title compound: LCMS m/z 195.88 [M+H]⁺, 197.86[M+2+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.25 (d, J=2.4 Hz, 1H), 7.69 (dd,J=9.6, 4.8 Hz, 1H), 7.46-7.42 (m, 1H).

Step B.6-fluoro-2-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile

To a solution of the title compound from Example 2 Step D (0.053 g,0.202 mmol) and the title compound from Example 4 Step A (0.033 g, 0.169mmol) in tetrahydrofuran (0.84 mL) were added palladium acetate (0.0038g, 0.017 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl(0.014 g, 0.034 mmol), and potassium phosphate tribasic (0.107 g, 0.506mmol). The resulting mixture was heated at 100° C. for 18 hours, thenfiltered with the aid of ethyl acetate and concentrated under reducedpressure. Purification by flash chromatography on silica gel (80%acetone in hexanes) provided the title compound: LCMS m/z 296.96[M+11]⁺; ¹H NMR (500 MHz, CDCl₃) δ 9.28 (d, J=1.9 Hz, 1H), 8.87 (d,J=2.0 Hz, 1H), 8.55 (t, J=2.1 Hz, 1H), 8.35 (s, 1H), 7.79 (dd, J=9.8,4.7 Hz, 1H), 7.45-7.41 (m, 1H), 1.98 (br s, 1H), 1.69 (s, 6H).

Step A. 2-(5-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol

To a flask containing 3-acetyl-5-bromopyridine (2.27 g, 11.4 mmol) wasadded a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran(0.5 M, 40 mL, 20 mmol) at 0° C. A solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added,and the reaction stirred at room temperature until the reaction wascomplete. The reaction was then concentrated under reduced pressure,diluted with ethyl acetate, and washed with water and saturated aqueoussodium bicarbonate solution. The organic layer was separated, dried oversodium sulfate, filtered and concentrated to give a residue that waspurified by flash chromatography on silica gel (10-50% ethyl acetate inhexanes) to provide the racemic title compound: LCMS m/z 269.85[M+2+H]⁺; ¹H NMR (500 MHz, CD₃OD) δ 8.70 (s, 1H), 8.65 (1H), 8.13 (s,1H), 1.81 (s, 3H). The racemic title compound was resolved bysupercritical fluid chromatography on a chiral AD column, eluting with10% ethanol:CO₂. Data for enantiomer A: LCMS m/z 271.85 [M+H]⁺; ¹H NMR(500 MHz, CDCl₃) 8.71 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.10 (s, 1H),1.82 (s, 3H). Data for enantiomer B: LCMS m/z 271.83 [M+H]⁺; ¹H NMR (500MHz, CDCl₃) 8.71 (s, 1H), 8.68 (s, 1H), 8.10 (s, 1H), 1.81 (s, 3H).

Step B. [5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]boronicacid

A vial containing the title compound from Intermediate 2 Step A[enantiomer B (0.647 g, 2.40 mmol)], bis(pinacolato)diboron (1.22 g,4.79 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.439 g, 0.479mmol), tricyclohexylphosphine (0.269 g, 0.958 mmol) and potassiumacetate (0.705 g, 7.19 mmol) in 1,4-dioxane (12 mL) was flushed withnitrogen, sealed tightly and heated to 80° C. overnight. The reactionwas then passed through a syringe filter and concentrated under reducedpressure to provide the title compound: LCMS m/z 235.95 [M+H]⁺.

The compounds in Table 1 were all prepared using chemistry described inthe preparation of Examples 14 and Intermediate 1.

TABLE 1 Example Structure Name LCMS 5

6-fluoro-2-(pyridin-3 - yl)imidazo[1,2-a]pyridine 214.1 6

6-fluoro-2-(4-methylpyridin-3- yl)imidazo[1,2-a]pyridine 228.0 7

6-fluoro-2-(5-methylpyridin-3- yl)imidazo[1,2-a]pyridine 228.0 8

2-(5-(6-fluoroimidazo[1,2- a]pyridin-2-yl)pyridin-3- yl)propan-2-ol274.0 9

1,1,1-trifluoro-2-(5-(6- fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol 326.0 10

8-fluoro-2-(5-methylpyridin-3- yl)imidazo[1,2-a]pyridine 228.0 11

6-chloro-2-(5-fluoropyridin-3- yl)imidazo[1,2-a]pyridine 248.1 12

6-chloro-7-fluoro-2-(5- fluoropyridin-3-yl)imidazo[1,2- a]pyridine 266.113

2-(isoquinolin-4-yl)imidazo[1,2- a]pyridine-7-carbonitrile 271.0 14

6-methyl-2-(6-methylpyridin-3- yl)-3-methylimidazo[1,2- a]pyridine 238.015

8-methyl-2-(6-methylpyridin-3- yl)-3-methylimidazo[1,2- a]pyridine 238.016

7-methyl-2-(6-methylpyridin-3- yl)-3-methylimidazo[1,2- a]pyridine 238.017

6-fluoro-3-methyl-2-(pyridin-3- yl)imidazo[1,2-a]pyridine 228.2 18

6-fluoro-3-methyl-2-(5- methoxypyridine-3- yl)imidazo[1,2-a]pyridine258.0 19

6-fluoro-3-methyl-2-(5- methylpyridin-3-yl)imidazo[1,2- a]pyridine 242.020

6-fluoro-3-methyl-2-(4- methylpyridin-3-yl)imidazo[1,2- a]pyridine 242.021

5-(6-fluoro-3- methylimidazo[1,2-a]pyridin-2- yl)nicotinonitrile 253.022

3-methyl-6-fluoro-2-(5- (trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine 296.0 23

2-(5-(6-fluoro-3- methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol 286.2 24

1,1,1-trifluoro-2-(5-(6-fluoro-3- methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol 340.0 25

4-(6-fluoro-3-ethylimidazo[1,2- a]pyridin-2-yl)isoquinoline 278.2 26

7-fluoro-2-(5-fluoropyridin-3- yl)-3-methylimidazo[1,2- a]pyridine 246.027

3-cyclopropyl-6-methyl-2-(4- methylpyridin-3-yl)imidazo[1,2- a]pyridine264.2 28

3-cyclopropyl-6-fluoro-2- (pyridin-3-yl)imidazo[1,2- a]pyridine 254.0 29

3-cyclopropyl-6-fluoro-2-(5- methylpyridin-3-yl)imidazo[1,2- a]pyridine268.2 30

3-cyclopropyl-6-fluoro-2-(6- methylpyridin-3-yl)imidazo[1,2- a]pyridine268.2 31

3-cyclopropyl-6-fluoro-2-(5- fluoropyridin-3-yl)imidazo[1,2- a]pyridine272.0 32

3-cyclopropyl-6-fluoro-2-(5- fluoro-4-methylpyridin-3-yl)imidazo[1,2-a]pyridine 286.2 33

3-cyclopropyl-2-(4-ethyl-5- fluoropyridin-3-yl)-6-fluoroimidazo[1,2-a]pyridine 300.2 34

3-cyclopropyl-6-fluoro-2-(5- methoxypyridin-3-yl)imidazo [1,2-a]pyridine284.0 35

3-cyclopropyl-6-fluoro-2-(5- (trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine 322.2 36

5-(3-cyclopropyl-6- fluoroimidazo[1,2-a]pyridin-2- yl)nicotinonitrile278.9 37

2-(5-(3-cyclopropyl-6- fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol 312.0 38

2-(5-(3-cyclopropyl-6- fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)-1,1,1- trifluoropropan-2-ol 366.2 39

3-cyclopropyl-6-fluoro-2-(5- phenylpyridin-3-yl)imidazo[1,2- a]pyridine330.0 40

methyl 5-(3-cyclopropyl-6- fluoroimidazo[1,2-a]pyridin-2- yl)nicotinate312.0 41

4-(3-cyclopropyl-6- fluoroimidazo[1,2-a]pyridin-2- yl)isoquinoline 304.242

6-chloro-3-cyclopropyl-2-(5- fluoropyridin-3-yl)imidazo[1,2- a]pyridine288.1 43

6-chloro-3-cyclopropyl-7-fluoro- 2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine 306.1 44

4-(3-cyclopropyl-8- fluoroimidazo[1,2-a]pyridin-2- yl)isoquinoline 264.045

2-{5-[3-cyclopropyl-6- (trifluoromethyI)imidazo[1,2-a]pyridin-2-yl]pyridin-3-yl}- 1,1,1-trifluoropropan-2-ol 416.1 46

3-cyclopropyl-2-[5-(1,1,1- trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]imidazo[1,2- a]pyridine-6-carbonitrile 373.1

Assay Description and Results

Methods for V79-Human-CYP11B2 and V79-Human-CYP11B1 Assays:

V79 cell lines stably expressing the either the human CYP11B2 or thehuman CYP11B 1 enzyme were generated using a standard transfectionprotocol. V79 cells were transfected with plasmidspTriEx3-Hygro-hCyp11B2 or pTriEx3-Hygro-hCyp11B1 using Lipofectamine2000reagent. V79 cells that stably express the human CYP11B2 or humanCYP11B1 enzyme were selected for and maintained in DMEM supplementedwith 10% FBS and 400 μg/mL hygromycin for 2 weeks. Single cell cloneswere generated by infinite dilution in DMEM supplemented with 10% FBSand 400 μg/mL hygromycin until single colonies were obtained. ClonesV79-hCYP11B2-CLE9 and V79-hCYP11B1-CL8C7, were determined to produce themost aldosterone and cortisol, respectively, and were selected forinhibitor screening. For testing of inhibitors, cells were harvested at80% confluency with 0.5% Trypsan-EDTA, washed once in PBS, andreconstituted in DMEM+0.1% BSA media at a cell concentration of 600,000cells/mL for the CYP11B2 assay and 280,000 cells/mL for the CYP11B1assay. 25 μL of cells were added to a 384 well tissue culture treatedplate and mixed with 0.3 μL of inhibitor or DMSO (1% final DMSOconcentration) for 1 hour at 37° C., 5% CO₂. After pre-incubation withinhibitor, the reaction was initiated by adding 5 μL of substrate (finalconcentration of 125 nM 11-deoxycorticosterone for the CYP11B2 assay or250 nM 11-deoxycortisol for the CYP11B1 assay). The reaction was carriedout for 3 hours at 37° C., 5% CO₂ and was stopped by harvesting thesupernatants. The amount of product in the supernatant (aldosterone forCYP11B2 assay and cortisol for the CYP11B1 assay) was measured usingHTRF-based assay kit (Aldosterone HTRF-CisBio#64ALDPEB, CortisolHTRF-CisBio #63IDC002-CORT). IC₅₀s for the inhibitor were determined byplotting the amount of product formed against the concentration ofinhibitor using sigmoidal dose-response curve (variable slope) fit inGraphPad.

The compounds of Examples 1-46 were tested in the V79-Human-CYP11B2 cellassay and found to have IC₅₀s for inhibition of human CYP11B2 of lessthan 10000 nM. A sub-group of compounds had IC₅₀s less than or equal to250 nM, and a further sub-group of compounds had IC₅₀s less than orequal to 50 nM.

The compounds of Examples 1-46 were also tested in the V79-Human-CYP11B1cell assay. A sub-group of compounds were at least 10-fold moreselective for inhibition of CYP11B2 as compared to CYP11B1, and afurther sub-group of compounds were at least 30-fold more selective forinhibition of CYP11B2. Representative examples of data collected forcompounds of the present invention are shown in Table 2 below.

TABLE 2 V79 Human V79 Human CYP11B2 CYP11B1 Example IUPAC Name IC₅₀ (nM)IC₅₀ (nM) 6 6-fluoro-2-(4-methylpyridin-3- 22.4   63*yl)imidazo[1,2-a]pyridine 7 6-fluoro-2-(5-methylpyridin-3- 56.2   60*yl)imidazo[1,2-a]pyridine 14 6-methyl-2-(6-methylpyridin-3- 9.1 2399yl)-3-methylimidazo[1,2-a]pyridine 15 8-methyl-2-(6-methylpyridin-3- 3.8 646 yl)-3-methylimidazo[1,2-a]pyridine 167-methyl-2-(6-methylpyridin-3- 204   68* yl)-3-methylimidazo[1,2-a]pyridine 18 6-fluoro-3-methyl-2-(5- 0.3    32.4methoxypyridin-3-yl)imidazo[1, 2-a]pyridine 19 6-fluoro-3-methyl-2-(5-0.45    40.7 methylpyridin-3-yl)imidazo[1,2- a]pyridine 206-fluoro-3-methyl-2-(4- 2.2  135 methylpyridin-3-yl)imidazo[1,2-a]pyridine 25 4-(6-fluoro-3-ethylimidazo[1,2- 0.1    14.8a]pyridin-2-yl)isoquinoline 26 7-fluoro-2-(5-fluoropyridin-3- 4.7  912yl)-3-methylimidazo[1,2- a]pyridine 28 3-cyclopropyl-6-fluoro-2- 23.4  76* (pyridin-3-yl)imidazo[1,2- a]pyridine 293-cyclopropyl-6-fluoro-2-(5- 1.5  589 methylpyridin-3-yl)imidazo[1,2-a]pyridine 30 3-cyclopropyl-6-fluoro-2-(6- 3.2 1072methylpyridin-3-yl)imidazo[1,2- a]pyridine 313-cyclopropyl-6-fluoro-2-(5- 10.7   67* fluoropyridin-3-yl)imidazo[1,2-a]pyridine 34 3-cyclopropyl-6-fluoro-2-(5- 4.5  759methoxypyridin-3-yl)imidazo[1, 2-a]pyridine 353-cyclopropyl-6-fluoro-2-(5- 7.1 1023 (trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine 38 2-(5-(3-cyclopropyl-6- 6.3 1122fluoroimidazo[1,2-a]pyridin-2- yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol 41 4-(3-cyclopropyl-6- 0.5    57.5fluoroimidazo[1,2-a]pyridin-2- yl)isoquinoline 44 4-(3-cyclopropyl-8-14.5 2188 fluoroimidazo[1,2-a]pyridin-2- yl)isoquinoline *= % inhibitionat 10 μM

While the invention has been described with reference to certainparticular embodiments thereof, numerous alternative embodiments will beapparent to those skilled in the art from the teachings describedherein. Recitation or depiction of a specific compound in the claims(i.e., a species) without a specific stereoconfiguration designation, orwith such a designation for less than all chiral centers, is intended toencompass the racemate, racemic mixtures, each individual enantiomer, adiastereoisomeric mixture and each individual diastereomer of thecompound where such forms are possible due to the presence of one ormore asymmetric centers. All patents, patent applications andpublications cited herein are incorporated by reference in theirentirety.

We claim:
 1. A compound of the structural formula

or a pharmaceutically acceptable salt thereof wherein: Ring A isattached to Ring B via positions D and E and is:

D is C; E is N; R¹ is H or alkyl; R² is H; halogen; —CN; —OR⁷;—N(R¹⁰)C(O)OR⁷; —NR¹¹R¹²; —C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)OR⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, NR⁸R⁹, CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; aryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; R³ is H; halogen; —CN; alkyloptionally substituted one or more times by halogen or cycloalkyloptionally substituted once or twice by alkyl or halogen; cycloalkyloptionally substituted once or twice by alkyl or halogen; or —C(O)OR⁷;R⁴ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷; —C(O)OR⁷;—C(O)N(R⁸)(R⁹); —C(O)OR⁷; —N(R¹⁰)S(O)₂—OR⁷; —S(O)_(n)—R⁷; alkyloptionally substituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —N(R¹⁰)S(O)₂—R⁷ or —S(O)OR⁷;cycloalkyl optionally substituted one or more times by halogen, alkyl,haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷or —S(O)_(m)—R⁷; aryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—OR⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹;—N(R¹⁰)C(O)OR⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷; —C(O)OR⁷; —N(R¹⁰)S(O)₂—OR⁷;—S(O)_(n)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—N(R¹⁰)S(O)₂—R⁷, or —S(O)—R⁷; cycloalkyl optionally substituted one ormore times by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(n)—R⁷; aryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one or more timesby halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)OR⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—OR⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; or R⁴ and R⁵ are joined together to form a 5-to 7-membered carbocyclic or heterocyclic ring that is fused to thepyridyl ring to which R⁴ and R⁵ are attached, wherein the ring formed byR⁴ and R⁵ is optionally substituted by 1 to 3 R⁶; R⁶ is independently H;halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷; —C(O)N(R⁷)(R⁸);—C(O)N(R⁸)(R⁹); —C(O)OR⁷; —S(O)_(m)—R⁷; alkyl optionally substituted oneor more times by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)OR⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷,—NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;aryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸),—C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionally substituted one ormore times by halogen, alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; R⁷is independently H; alkyl optionally substituted one or more times byhalogen, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰or —S(O)_(m)—R¹⁰; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; aryl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰,—NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—RR¹⁰; or heteroaryl optionally substituted one or more timesby halogen, alkyl, haloalkyl, cycloalkyl, —OR¹⁰, —NR⁸R⁹, —CN,—N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; R⁸ isindependently H or alkyl; R⁹ is independently H or alkyl; or R⁸ and R⁹are joined together with the nitrogen to which they are attached to forma saturated 5- to 7-membered heterocyclic ring; R¹⁰ is independently Hor alkyl; R¹¹ is independently H; alkyl optionally substituted one ormore times by halogen, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyl optionally substituted one or moretimes by halogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁸ or —S(O)_(m)—R⁸; aryl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted one ormore times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; R¹² isindependently H; alkyl optionally substituted one or more times byhalogen, —OR⁷, —NR⁸R⁹, CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, CN, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁸ or —S(O)_(m)—R⁸; aryl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more times byhalogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; a is 0, 1, 2, 3 or 4; n is 1or 2; and m is 0, 1 or
 2. 2. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula Formula II

wherein: R² is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl,OR⁷ or phenyl optionally substituted by halogen; R³ is H, halogen, —CN,alkyl or cycloalkyl; R⁴ is H, halogen, —CN, alkyl or cycloalkyl; R⁵ is:i.) H, halogen, —CN, alkyl, —OR⁷, haloalkyl or phenyl optionallysubstituted by halogen or haloalkyl; ii.) C(O)OR⁷; or iii.) a group ofthe formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3 —F;—OC₁-C₃-alkyl; —N(H)S(O)₂—C₁-C₃-alkyl; optionally substituted with 1 to3 —F; or —N(H)C(O)C₁-C₃-alkyl, optionally substituted with 1 to 3 —F; R⁷is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionally substituted byhalogen; and a is 0, 1 or
 2. 3. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula

wherein: R¹ is independently H or alkyl; R² is independently halogen,—CN, alkyl, haloalkyl, cycloalkyl, OR⁷ or phenyl optionally substitutedby halogen; R³ is H, halogen, —CN, alkyl or cycloalkyl; R⁴ is H,halogen, —CN, alkyl or cycloalkyl; R⁵ is: i.) H, halogen, —CN, alkyl,—OR⁷, —C(O)OR⁷, haloalkyl or phenyl optionally substituted by halogen orhaloalkyl; or ii.) a group of the formula:

where: R^(a) is H, OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(b) is H, —OH, or —C₁-C₃-alkyl optionally substituted with 1 to3 —F; R^(c) is —C₁-C₃-alkyl optionally substituted with 1 to 3 —F;—OC₁-C₃-alkyl; —N(H)S(O)₂—C₁-C₃-alkyl, optionally substituted with 1 to3 —F; or —N(H)C(O)C₁-C₃-alkyl, optionally substituted with 1 to 3 —F; R⁷is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionally substituted byhalogen; and a is 0, 1 or
 2. 4. The compound as defined in claim 1 or apharmaceutically acceptable salt thereof, which has the structuralformula

wherein: R² is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl,OR⁷ or phenyl optionally substituted by halogen; R³ is H, halogen, —CN,alkyl or cycloalkyl; R⁶ is alkyl or halo; a is 0, 1 or 2; and b is 0, 1or
 2. 5. The compound as defined in claim 1 or a pharmaceuticallyacceptable salt thereof, which has the structural formula

wherein: R² is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl,OR⁷ or phenyl optionally substituted by halogen; R³ is H, halogen, —CN,alkyl or cycloalkyl; R⁶ is alkyl or halo; a is 0, 1 or 2; and b is 0, 1or
 2. 6. The compound as defined in claim 1 which is6-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;8-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;4-(6-fluoro-3-ethylimidazo[1,2-a]pyridin-2-yl)isoquinoline;6-fluoro-3-methyl-2-(5-methoxypyridin-3-yl)imidazo[1,2-a]pyridine;6-fluoro-3-methyl-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;6-fluoro-3-methyl-2-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridine7-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;3-cyclopropyl-6-fluoro-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;3-cyclopropyl-6-fluoro-2-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine;2-(5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;3-cyclopropyl-6-fluoro-2-(5-methoxypyridin-3-yl)imidazo[1,2-a]pyridine;3-cyclopropyl-6-fluoro-2-(5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine;4-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)isoquinoline;3-cyclopropyl-6-fluoro-2-(pyridin-3-yl)imidazo[1,2-a]pyridineN-((5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)methyl)ethanesulfonamide;3-cyclopropyl-6-fluoro-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;4-(3-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)isoquinoline;6-fluoro-2-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridine;6-fluoro-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine; or apharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula I as defined in claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of Formula I as defined in claim 1 or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of at least one additional therapeutic agent and apharmaceutically acceptable carrier.
 9. A method for the treatment,amelioration or prevention of one or more conditions associated withinhibiting CYP11B2, which comprises administering a therapeuticallyeffective amount at least one compound of Formula I as defined in claim1 or a pharmaceutically acceptable salt thereof to a mammal in need ofsuch treatment.
 10. The method according to claim 9 wherein theconditions that could be treated ameliorated or prevented by inhibitingCYP11B2 are The method according to claim 9 wherein the conditions thatcould be treated ameliorated or prevented by inhibiting CYP11B2 arehypertension, heart failure such as congestive heart failure, diastolicdysfunction, left ventricular diastolic dysfunction, heart failure,diastolic dysfunction, left ventricular diastolic dysfunction, diastolicheart failure, systolic dysfunction, hypokalemia, renal failure,restenosis, syndrome X, nephropathy, post-myocardial infarction,coronary heart diseases, increased formation of collagen, fibrosis andremodeling following hypertension and endothelial dysfunction,cardiovascular diseases, renal dysfunction, liver diseases, vasculardiseases, cerebrovascular diseases, retinopathy, neuropathy,insulinopathy, endothelial dysfunction, ischemia, myocardial andvascular fibrosis, myocardial necrotic lesions, vascular damage,myocardial necrotic lesions, vascular damage, myocardial infarction,left ventricular hypertrophy, cardiac lesions, vascular wallhypertrophy, endothelial thickening or fibrinoid necrosis of coronaryarteries.
 11. A method for inhibiting CYP11B2 in a mammal in needthereof which comprising administering to said mammal an effectiveamount of a compound of the structural formula

or a pharmaceutically acceptable salt thereof wherein: Ring A isattached to Ring B via positions D and E and is:

D is C; E is N; R¹ is H or alkyl; R² is H; halogen; —CN; —OR⁷;—N(R¹⁰)C(O)OR⁷; —NR¹¹R¹²; —C(O)R⁷; —C(O)N(R¹¹)(R¹²); —C(O)OR⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —OR⁷, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; aryloptionally substituted one or more times by halogen, alkyl, haloalkyl,cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,or —S(O)_(m)—R⁷; or heteroaryl optionally substituted one or more timesby halogen, alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹,N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; R³ is H;halogen; —CN; alkyl optionally substituted one or more times by halogenor cycloalkyl optionally substituted once or twice by alkyl or halogen;cycloalkyl optionally substituted once or twice by alkyl or halogen; or—C(O)OR⁷; R⁴ is H; halogen; —CN; —OR⁷; —NR⁸R⁹; —N(R¹⁰)C(O)OR⁷; —C(O)R⁷;—C(O)N(R⁸)(R⁹); —C(O)OR⁷; —N(R¹⁰)S(O)₂—R⁷; —S(O)_(n)—⁷; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷, —N(R¹⁰)S(O)₂—R⁷ or —S(O)_(n)R⁷;cycloalkyl optionally substituted one or more times by halogen, alkyl,haloalkyl, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R⁵ is H; halogen; —CN; —OR⁷; —NR⁸R⁹;—N(R¹⁰)C(O)OR⁷; —C(O)N(R⁸)(R⁹); —C(O)R⁷; —C(O)OR⁷; —N(R¹⁰)S(O)₂—OR⁷;—S(O)_(n)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, —NR⁸R⁹, —CN, —N(R¹¹)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷,—N(R¹⁰)S(O)₂—R⁷, or —S(O)_(n)—R⁷; cycloalkyl optionally substituted oneor more times by halogen, alkyl, haloalkyl, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷,—C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; aryl optionally substitutedone or more times by halogen, alkyl, haloalkyl, cycloalkyl, —CN,—NR⁸R⁹—N(R¹⁰)C(O)(R⁷), —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷;heterocycloalkyl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; or heteroaryl optionally substituted one ormore times by halogen, alkyl, haloalkyl, cycloalkyl, —CN, —NR⁸R⁹,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; or R⁴ and R⁵are joined together to form a 5- to 7-membered carbocyclic orheterocyclic ring that is fused to the pyridyl ring to which R⁴ and R⁵are attached, wherein the ring formed by R⁴ and R⁵ is optionallysubstituted by 1 to 3 R⁶; R⁶ is independently H; halogen; —CN; —OR⁷;—NR⁸R⁹; —N(R¹⁰)C(O)R⁷; —C(O)N(R⁷)(R⁸); —C(O)N(R⁸)(R⁹); —C(O)OR⁷;—S(O)_(m)—R⁷; alkyl optionally substituted one or more times by halogen,—OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or—S(O)_(m)—R⁷; cycloalkyl optionally substituted one or more times byhalogen, alkyl, haloalkyl, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; aryl optionally substituted one or more timesby halogen, alkyl, haloalkyl, cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R⁷ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR¹⁰, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O), —R¹⁰; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OH, —OR¹⁰, —NR⁸R⁹, —CN, —N(R¹⁰)C(O)R¹⁰,—C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or —S(O)_(m)—R¹⁰; or heteroaryl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl,—OR¹⁰, —NR⁸R⁹, —CN, —N(R⁹)C(O)R¹⁰, —C(O)N(R⁸)(R⁹), —C(O)OR¹⁰ or—S(O)_(m)—R¹⁰; R⁸ is independently H or alkyl; R⁹ is independently H oralkyl; or R⁸ and R⁹ are joined together with the nitrogen to which theyare attached to form a saturated 5- to 7-membered heterocyclic ring; R¹⁰is independently H or alkyl; R¹¹ is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; R¹² is independently H; alkyl optionallysubstituted one or more times by halogen, —OR⁷, —NR⁸R⁹, —CN,—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; cycloalkyloptionally substituted one or more times by halogen, alkyl, haloalkyl,—OR⁷, —NR⁸R⁹, —CN, N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁸ or—S(O)_(m)—R⁸; aryl optionally substituted one or more times by halogen,alkyl, haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹—N(R¹⁰)C(O)(R⁷),—C(O)N(R⁷)(R⁸), —C(O)OR⁷ or —S(O)_(m)—R⁷; heterocycloalkyl optionallysubstituted one or more times by halogen, alkyl, haloalkyl, —OR⁷, —CN,—NR⁸R⁹—N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹), —C(O)OR⁷ or —S(O)_(m)—R⁷; orheteroaryl optionally substituted one or more times by halogen, alkyl,haloalkyl, cycloalkyl, —OR⁷, —CN, —NR⁸R⁹, —N(R¹⁰)C(O)R⁷, —C(O)N(R⁸)(R⁹),—C(O)OR⁷ or —S(O)_(m)—R⁷; a is 0, 1, 2, 3 or 4; n is 1 or 2; and m is 0,1 or 2.